Patients were assigned to 75 mg eluxadoline (n=810), 100 mg eluxadoline (n=809), or placebo (n=809) twice daily for 26 weeks (IBS3002) or 52 weeks (IBS3001). Based on results from both trials, patients who received eluxadoline had higher responder rates than patients taking placebo for U.S. Food and Drug Administration (at 12 weeks) and European Medicines Agency (at 26 weeks) primary (concurrent improvement in abdominal pain and stool consistency from baseline for at least 50% of days) and secondary endpoints (which included improvements in global symptoms and quality of life).

The treatment effects of eluxadoline over placebo were noted within the first week of treatment and sustained throughout the 26-week assessment period. Pooled results after 12 weeks of therapy showed beneficial response in 16.7% of patients taking placebo, 26.2% of those taking eluxadoline 75 mg twice daily, and 27.0% of those taking eluxadoline 100 mg twice daily -- corresponding to a number-needed-to-treat of around 10. While eluxadoline outperformed placebo, the overall response was low: less than a third of patients met the primary outcome. This low response rate, similar to that seen in clinical trials for other IBS-D medications (i.e., alosetron and rifaximin), highlights the challenging nature of IBS-D treatment.

The most common side effects, which occurred in less than 10% of patients, were constipation, nausea, and abdominal pain. Pancreatitis developed in five of 1,666 patients (0.3%), and abdominal pain with elevated liver enzyme levels developed in eight of 1,666 patients (0.5%). Three of the episodes of pancreatitis were associated with significant alcohol consumption. Sphincter of Oddi spasm was found to be the cause of one patient with pancreatitis and all eight patients who had abdominal pain with elevated liver enzymes, and occurred only in patients who had undergone a prior cholecystectomy.

In two controlled phase III trials published in the New England Journal of Medicine, more patients receiving eluxadoline than placebo met the studies' primary composite endpoints of simultaneous reduced abdominal pain and improved stool consistency on the same days.

The drug's action on the three receptors thus distinguishes it from the IBS drug loperamide, which acts only on the mu receptor. "This combination may have beneficial effects in reducing constipation compared with the pure mu-opioid receptor agonists," said Anthony J. Lembo, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, in an interview with MedPage Today. "And animal models suggested this combination may lead to further improvement in hypersensitivity, particularly pain."

Other IBS-D drugs such as the 5-HT3 antagonist alosetron (Lotronex) "have fairly high prevalence of rates of constipation, particularly at higher doses," he continued. "Eluxadoline adds another treatment option for patients suffering from IBS-D."

In two separate studies, Lembo and his colleagues randomized 2,427 adults, ages 18 to 80, with IBS-D according to Rome III diagnostic criteria. Participants were recruited from multiple centers in the U.S., Canada, and the U.K. during 2011 to 2014.

The overall cohort was about two-thirds female, and the mean age across study groups was about 45. More than 85% were white, and the mean body mass index was close to 30. Mean abdominal pain scores were approximately 6 (with 10 the worst), and the average number of daily bowel movements approached five. Scores on the 34-item IBS Quality of Life Questionnaire ranged from 44.1 to 50.6 out of 100, and the mean IBS-D Global Symptom score was 2.8 or 2.9.

Patients used an interactive voice response system as an electronic diary to record their symptoms.

"The treatment effect of eluxadoline over placebo was observed within the first week and was maintained throughout the 26-week assessment period," Lembo and colleagues wrote.

For weeks 1 through 12, more patients in the eluxadoline arms than in the placebo arms reached the primary endpoint. In the first trial of 52 weeks (1,282 patients), response was 23.9% on the 75-mg dose and 25.1% on the 100-mg dose versus 17.1% on placebo (P=0.01 and P=0.004, respectively). In the 26-week second study (1,146 patients), response was 28.9% and 29.6%, respectively, in the two treatment arms versus 16.2% for placebo (P<0.001 for both comparisons).

For weeks 1 through 26, the corresponding rates in the 52-week study were 23.4% and 29.3% versus 19% (P=0.11 and P<0.001, respectively), while the rates in the 26-week study were 30.4% and 32.7% versus 20.2% (P=0.001 and P<0.001, respectively).

Treatment effects on symptom relief were similar to those reported with alosetron and the antibiotic rifaximin.

Eluxadoline was also significantly superior to placebo for secondary endpoints such as global assessments of symptom relief and quality of life, particularly at the 100-mg dose.

"We need more effective treatments for IBS because one treatment does not work in all patients, which is likely due to the fact that IBS is a multifactorial condition," said Lin Chang, MD, of UCLA's David Geffen School of Medicine in Los Angeles. "Having more treatment options for IBS helps to increase the awareness, diagnosis, and treatment of this condition."

Chang noted that, interestingly, while eluxadoline simultaneously improved diarrhea and abdominal pain, it was not significantly superior to placebo when measured by the prespecified secondary outcome of a minimum 30% reduction in the worst abdominal pain. Eluxadoline did, however, show superior efficacy at higher thresholds of pain improvement, for example, at 40% or higher and 50% or higher. "Future research needs to be directed at better disease phenotyping of IBS patient subgroups who respond to a specific treatment, understanding pathophysiologic processes, and identifying novel drug targets," Chang said.

Compared with placebo, the most common adverse events at both doses of eluxadoline were nausea (8.6% and 7.5% versus 5.1% for placebo), constipation (7.4% and 8.6% versus 2.5%), and abdominal pain (5.8% and 7.2% versus 4.1%).

Pancreatitis developed in five patients in the experimental arms: two at 75 mg and three at 100 mg. In a combined 1,666-patient safety population of participants who had received at least one dose of either eluxadoline or placebo, pancreatitis developed in 0.3%, and there were eight cases of abdominal pain with elevated levels of hepatic enzymes (0.5%).

In a 2013 paper, Lembo and colleagues had reported that eluxadoline's simultaneous agonism of the mu-opioid receptor and antagonism of the delta-opioid receptor reduced abdominal pain and diarrhea versus placebo in a phase II study -- again without widespread constipation.

The authors called for studies to identify subpopulations of patients with IBS-D who will benefit most from the drug. "So far, no biomarkers have been identified, but two biomarkers have been found that distinguish between post-gastroenteritis IBS and inflammatory bowel disease," said Lembo. The commercially available IBSchek kit tests for antibodies to cytolethal distending toxin B and to the gut endothelial protein vinculin with which it interacts.

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